Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

Abstract

In a continuing study of potent bifunctional anti-HIV agents, we rationally designed a novel chimeric inhibitor utilizing thymidine (THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a polymethylene linker (ALK). The nucleoside, 5′-hydrogen-phosphonate (H-phosphonate), and 5′-triphosphate forms of this chimeric inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (11) and the H-phosphonate (10) derivatives inhibited RT polymerization with an IC 50 value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (9) and Hphosphonate (10) derivatives reduced HIV replication in a cellbased assay with low nanomolar antiviral potencies.

Synthesis and Biophysical Investigations of Oligonucleotides Containing Galactose-Modified DNA, LNA, and 2′-Amino-LNA Monomers

“…In the first step either ethylene glycol ( 2 ) or triethylene glycol ( 3 ) were attached to acetobromo-α- d -galactose ( 1 ), , and in the second step the primary hydroxy groups were converted to the corresponding carboxylic acids using TEMPO/TCCA oxidation in yields of 91% (for 6 ) and 78% (for 7 ). 5-Azidomethyl-5′- O -(4,4′-dimethoxytrityl)-2′-deoxyuridine ( 10 ) was synthesized according to known procedures − but optimized with respect to the acetyl deprotection step, for which we used sodium hydroxide in methanol/water instead of ammonium hydroxide as reported since we otherwise observed partial substitution of the azido group by an amino group. After 4,4′-dimethoxytrityl (DMTr) protection of the 5′-hydroxy group, the azido group of compound 10 was reduced to the corresponding amine using Staudinger conditions, and was subsequently coupled with the appropriate galactosyl carboxylic acid ( 6 and 7 ) in the presence of HATU.…”

“…Compound 10 was synthesized starting from thymidine ( 8 ) in five steps according to known procedures. 3′,5′-Di- O -acetyl-5-azidomethyl-2′-deoxyuridine ( 9 ) , was deprotected using 2 M NaOH in MeOH/H 2 O instead of concentrated aqueous ammonia as earlier reported …”

“…54 Compound 10 was synthesized starting from thymidine (8) in five steps according to known procedures. 3′,5′-Di-O-acetyl-5azidomethyl-2′-deoxyuridine (9) 53,55 was deprotected using 2 M NaOH in MeOH/H 2 O instead of concentrated aqueous ammonia as earlier reported. 53 5′-O-(4,4′-Dimethoxytrityl)-5-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxyacetami-do)methyl-2′-deoxyuridine (11).…”

Pharmacological Activity of Pyrazole Derivatives as an Anticonvulsant for Benefit against Epilepsy

“…The strategy is based on the assumption that after reaching the site, the linker will be degraded and both skeletons are free enough to act individually on different targets, that is, multi-targeted approach. This approach has been successfully attempted to control various diseases, such as Alzheimer's [20,21], cancer [22], malaria [23][24][25], HIV [26], and bacterial disease [27][28][29][30] where simultaneous inhibition of 2 or more receptors provides significant results and poses less chance of resistance.…”

Biological evaluation of inhibitors of reverse transcriptase from HIV type-1

“…Wide variety of drugs has been developed for HIV based on these studies is available in market. These HIV-1 drugs are divided in nucleoside (NRTIs, AZT, e.g., 3TC, and ddC) and non-nucleoside (NNRTIs e.g., nevirapine, delaviridine) reverse transcriptase inhibitors [1][2][3][4][5] . Non-nucleoside inhibitors are most widely used for the treatment of HIV-1-infection 6 .…”